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www.nature.com/scientificreports OPEN Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Defciency with Atypical Presentation Lina Ghaloul-Gonzalez1,2*, Al-Walid Mohsen 1,2, Anuradha Karunanidhi1, Bianca Seminotti1, Hey Chong3, Suneeta Madan-Khetarpal1,2, Jessica Sebastian1, Catherine Walsh Vockley1, Miguel Reyes-Múgica 4, Mark T. Vander Lugt 5 & Jerry Vockley1,2 Reticular dysgenesis is an autosomal recessive form of severe combined immunodefciency (SCID) that usually manifests in newborns. It is a unique example of an immune defciency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 (AK2) defciency. It is characterized by an early diferentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel AK2 homozygous mutation, c.622 T > C [p.Ser208Pro], was identifed in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient’s cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidifcation rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confrm the pathogenicity of the AK2 mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune defciency. We also describe other pathophysiological aspects of AK2 defciency not previously reported. Reticular dysgenesis (RD) (MIM267500; aleukocytosis) is an autosomal recessive form of severe combined immunodefciency (SCID) resulting from defects in the adenylate kinase 2, AK2, gene located on chromosome 1p35.1. Mitochondrial dysfuntion appears to be unique to AK2 defciency among the immune defciencies1–3. RD is one of the most rare forms of SCID and also one of the most severe due to lack of not only lymphocytes but also granulocytes, ofen leading to fatal neonatal sepsis1,4. Additionally, individuals with RD have hypoplasia of the thymus and secondary lymphoid organs1,4. Current treatment of RD is limited to hematopoietic stem cell transplantation (HSCT)4,5. AK2 is a phosphotransferase enzyme localized in the mitochondrial intermembrane space and catalyzes the reversible transfer of a phosphoryl group from ATP to AMP giving 2 ADP molecules. ADP is then transported into the mitochondrial matrix by the ADP-ATP carriers that, in exchange, export ATP synthesized by oxidative phosphorylation (OXPHOS) into the cytosol. Balanaced ADP production and transport is critical to cellular energy homeostais since OXPHOS activity is dependent on matrix ADP levels1,2. While nine adenylate kinase isoforms have been identifed in various tissues, AK2 is the only isoenzyme identifed in bone marrow white blood cells pregenitors, leading to the immune defciency in AK2 defcient patients1,2,6. AK2 is also expressed in the inner ear and its dysfunction is likely the cause of the hearing defects observed in patients with AK2 defciency1. In this study, an AK2 defciency identifed in a fve-year old Amish male with a history of immunodefciency is described as well as the cellular pathophysiology induced by this defect. 1Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. 2Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 3Division of Pulmonology, Allergy and Immunology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. 4Division of Pediatric Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. 5Division of Blood and Marrow Transplantation and Cellular Therapies, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. *email: [email protected] SCIENTIFIC REPORTS | (2019) 9:15739 | https://doi.org/10.1038/s41598-019-51922-2 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Figure 1. H&E staining of the bone marrow, Pedigree, AK2 gene and protein structure. (A) H&E staining of the bone marrow. Control; bone marrow from an age-matched individual showing adequate cellularity with all normal hemopoietic cell lines represented and without predominance of any particular lineage. Pre-Tx; pre-transplant bone marrow biopsy from the patient at 13 months of age before bone marrow transplant showing myeloid maturation only through the promyelocyte/myelocyte stage. Only occasional neutrophils were seen. Post-Tx; post-transplant bone marrow biopsy from afected patient afer bone marrow transplant showing normocellular bone marrow with trilineage hematopoiesis (all images at 100X). (B) Pedigree of the family identifed with mutations in the AK2 gene. Both parents and siblings are unafected and heterozygous for the mutation while the patient is homozygous. Ages are representative of the individual ages at the time of manuscript submission. Asterisk denotes the age of the patient when he died following bone marrow transplant complication. (C) Structure of the AK2 gene (GenBank: NM_001625), location of the Ser208Pro mutation relative to the polypeptide stretch, and homology alignment of the AK2 β-strands IV (L125-I129) and VII (G206-A212) regions. Te secondary structure assignments are according to the human AK2 crystal structure atomic coordinates, PDB 2C9Y, highlighted in pink boxes. Residues in bold capital letters are invariants in all species examined, only 13 are shown. Residues in capital letters (not bold) are highly conserved, and residues in small letters seem dispensable. Highlighted in green is the Ser208 position. (D) Ribbon representation of the AK2 protein 3D structure, PDB 2C9Y, with the position of Ser208 depicted (replaced with a Pro in the patient of this study), plus the position of other previously reported mutations in the AK2 protein. BATP (letters in yellow) is the ATP binding domain. Material and Methods Study design. Tis study focused on the Amish population for discovery of novel genetic disorders through whole exome sequencing. Te current patient was recruited into this research study afer extensive genetic testing failed to diagnose known causes of combined immune defciency. Consent. Informed consent was obtained and approved for all participants in accordance to the University of Pittsburgh IRB approved protocol #PRO11070174 for clinical genomic studies. For underaged participants, parental informed consent was obtained and approved. All methods were performed in accordance with the relevant guidelines and regulations outlined by the IRB. Whole exome sequencing on a research basis was ofered to the family who agreed to participate in the study. Case selection. Tis case was selected as part of a study to diagnose novel genetic disorders in the Amish population in western Pennsylvania. Te patient was recruited into this study because of his combined immune defciency of unknown etiology. Case description. A five-year old Old Order Amish male first presented at ten months of age with Haemophilus infuenza and Pseudomonas aeruginosa sepsis and pneumonia. At his frst presentation, he had neutropenia (ANC 1030 cells/µL), T and B cell lymphopenia (143 cell/µL and 15 cells/µL, respectively), and hypogammaglobulinemia (IgG of 211 mg/dL). Proliferation to phytohemagglutinin (PHA) was decreased (25.2%; normal >49.9%). Combo-Chip Array studies identifed a 16p11.2 duplication as well as regions of homozygosity on chromosomes 1, 2, and 10. Testing for immunodefciency syndromes in the Amish related to known founder mutations were normal. A bone marrow aspirate and biopsy at 13 months of age showed maturation arrest, which occurred primarily through the promyelocyte/myelocyte stage, showing only an occasional neutrophil (Fig. 1A), and the patient was started on G-CSF for neutropenia with adequate response. He developed bronchiectasis due SCIENTIFIC REPORTS | (2019) 9:15739 | https://doi.org/10.1038/s41598-019-51922-2 2 www.nature.com/scientificreports/ www.nature.com/scientificreports to recurrent pulmonary infections and at 3 years of age, he developed refractory primary CMV viremia. Because of this, he underwent a hematopoietic stem cell transplantation (HSCT) from a mismatched related donor (maternal) for combined immunodefciency. He engrafed with full donor chimerism; however, he developed neutropenia and complete recipient chimerism in the myeloid lineage by six months post-transplant with contin- ued complete donor chimerism in CD3+ cells. He was diagnosed with moderate to severe sensorineural hearing loss at 4 years of age with absent otoacostic emissions (OAEs) following an evaluation for abnormal speech. He had a history of right failed newborn hearing screen. He underwent a second HSCT from the same donor 2 years later, which was complicated by engrafment syndrome and severe veno-occlusive disease of the liver, which was ultimately fatal (see Supplementary Materials for complete clinical synopsis). Whole exome sequencing. DNA was extracted from blood samples from all six subjects (pedigree, Fig. 1B). Whole exome sequencing was performed on DNA samples from unafected parents and the afected patient by BGI Americas Corporation. Sequencing via the Illumina Hiseq. 2000 was performed with library construction using Agilent SureSelect Human All Exon V4 (51 Mb) with a target of 100X coverage per sample. FASTQ fles were delivered to us for analysis. Sequence analysis. Fastq files
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  • Blueprint Genetics Severe Combined Immunodeficiency Panel

    Blueprint Genetics Severe Combined Immunodeficiency Panel

    Severe Combined Immunodeficiency Panel Test code: IM0101 Is a 80 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of combined immunodeficiencies. The genes on this panel are included in the Primary Immunodeficiency Panel. About Severe Combined Immunodeficiency Severe combined immunedeficiencies (SCIDs) are a group of primary immunodeficiencies characterized by specific mutations in genes of T and B-lymphocyte systems and leading to little or no immune response. Different subtypes of SCIDs are characterized and subdivided by the presence of circulating T and B cells. T cells are absent or markedly decreased in the most types, but levels of B cells vary. In addition, both of these disease subgroups (T-B+ and T-B-) can occur with or without NK cells. Patients with SCID are susceptible to recurrent infections that can be fatal. The worldwide prevalence of SCID is estimated to be at least 1:100,000 births, while some genetically more homogenous populations may show markedly increased numbers. Mutations in IL2RG are the most common reason for SCIDs, explaining approximately 50% of all cases and close to 100% of X-linked cases. Availability 4 weeks Gene Set Description Genes in the Severe Combined Immunodeficiency Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ADA Severe combined immunodeficiency due to adenosine deaminase AR 49 93 deficiency AK2 Reticular dysgenesis AR 14 17 ATM Breast cancer, Ataxia-Telangiectasia AD/AR 1047 1109 BCL11B Immunodeficiency